clinical trial to evaluate the safety and efficacy of treosulfan based conditioning prior to allogeneic haematopoietic stem cell transplantation (hsct)

Conditions: Leukemia; Chronic Myeloid Leukemia; Myelodysplastic Syndrome; Diffuse Large Cell Lymphoma; Hodgkin Lymphoma; Chronic Lymphocytic Leukemia; Multiple Myeloma

Summary: this is a multicentric, non-randomized, non-controlled open-label phase ii trial to evaluate the safety and efficacy of treosulfan in a combination regimen with fludarabine as conditioning therapy prior to allogeneic stem cell transplantation (sct) in patients with haematological malignancies. the aim is to demonstrate a clinical benefit compared with historical data on intravenous busulfan (busulfextm, busilvextm), the only drug so far registered in the indication conditioning before allogeneic stem cell transplantation.


Eligibility criteria:
inclusion criteria: 1. patients with haematological malignancies, according to who classification, such as: * acute myeloid leukaemia -aml- in cr1 except "low-risk cases" defined by t(15;17), t(8;21), inv 16 or normal cytogenetics at diagnosis with flt3-itd negative and npm-1 positive, with no high risk clinical criteria * any aml beyond cr1 * acute lymphoblast leukaemia -all- in cr1 only if at "high risk" defined by cytogenetics as t(9;22), t(4;11) or for persistence of minimal residual disease (mrd) * any all beyond cr1 * chronic myeloid leukaemia -cml- in chronic phase (cp) or accelerated phase (ap) intolerant/not responsive to tk-inhibitors * myeloproliferative disorders -mpd- * myelodysplastic syndrome -mds- with intermediate or high risk international prognostic scoring system (ipss) * diffuse large cell lymphoma -dlcl- with a chemosensitive relapse or beyond cr1 * lymphoblastic and burkitt lymphoma with a chemosensitive relapse or beyond cr1 * mantle cell lymphoma -mcl- with a chemosensitive relapse or beyond cr1 * follicular lymphoma -fcl- with a chemosensitive relapse or beyond cr2 * hodgkin lymphoma -hd- with a chemosensitive relapse or beyond cr1 * chronic lymphocytic leukaemia -cll- at "poor risk" in cr1 or with a chemosensitive relapse * cll relapsing after high dose chemotherapy * t-cell non hodgkin lymphoma -t-nhl- in cr1 or beyond * multiple myeloma -mm- at high risk for cytogenetics or iss stage 3 in cr1 following high dose chemotherapy * mm at any relapse/progression except refractory disease 2. availability of an hla-identical sibling donor (mrd) or hla-identical unrelated donor (mud) * hla-identity defined by the following markers: a, b, drb1, dqb1 or a single or double cord blood unit (cb) with at least a 4 out of 6 hla-matching by the following markers: a, b and drb. a) identity between the 2 cb units and the recipient; b) two identical cb units with one or two mismatches with the recipient; c) two cb units with one mismatch between them and two mismatches with the recipient. we will prefer mismatches either for class i or for class ii antigens; we will avoid mismatches concerning both classes i and ii together. 3. target graft size (unmanipulated, preferably not cryopreserved) * bone marrow: 2 to 10 x 106 cd34+ cells/kg bw recipient or \> 2 x 108 nucleated cells/kg bw recipient or * peripheral blood: 4 to 10 x 106 cd34+ cells/kg bw recipient 4. age \> 18 and \< 70 years 5. karnofsky index \> 80 % 6. adequate contraception in female patients of child-bearing potential 7. written informed consent exclusion criteria: 1. secondary malignancies 2. previous allogeneic transplantation 3. hematopoietic cell transplantation-specific comorbidity index \> 4 (hct-ci sorror et al, appendix m) 4. known and manifested malignant involvement of the cns 5. active infectious disease 6. hiv- positivity or active hepatitis infection 7. impaired liver function (bilirubin \> upper normal limit; transaminases \> 3.0 x upper normal limit) 8. impaired renal function (creatinine-clearance \ 1.5 x upper normal limit). 9. pleural effusion or ascites \> 1.0 l 10. pregnancy or lactation 11. known hypersensitivity to treosulfan and/or fludarabine 12. participation in another experimental drug trial within 4 weeks before day -6 13. non-co-operative behaviour or non-compliance 14. psychiatric diseases or conditions that might impair the ability to give informed consent